In this project we are coupling genetic and environmental studies in selected families and twin pairs with disorders such as multiple sclerosis, Parkinson's disease, and Alzheimer's disease, in an effort to distinguish specific contributing factors. A multi-disciplinary twin study of Parkinson's disease has led to formulation of an etiologic theory we term the "initial neuron number" hypothesis. Since neurons in the substantia nigra are not known to regenerate but rather appear to die off at a constant rate during adulthood, starting life with a reduced number of these critical neurons may be one predisposing factor to eventual development of the disorder. A study similar in design involving twins with dementia of the Alzheimer's types also indicates environmental factors must be involved in some forms of the disorder. An autosomal dominant, hereditary leukoencephalopathy simulating MS with onset at about age 35 is under study in a kindred with over 20 affected. Derangement of the autonomic nervous system is often seen early in the course and when recognized clinically, serves to distinguish this single gene disorder from multiple sclerosis. Computerized tomographic scan changes of the brain are characteristic, even in early cases.